Open-label, multi-center, Phase III clinical trial to compare the effectiveness and tolerability of a three-month (12-dose) regimen of weekly rifapentine and isoniazid (3RPT/INH) to the effectiveness of a nine-month (270-dose)regimen of daily isoniazid (9INH) to prevent tuberculosis (TB) among high-risk tuberculin skin-test reactors, including children and HIV-infected persons, who require treatment of latent TB infection (LTBI).

Further study details as provided by Centers for Disease Control and Prevention:

Primary Outcome Measures:

Cumulative Rate of Culture-Confirmed TB Disease in Participants ≥18 Years of Age AND Culture-Confirmed or Probable (Clinical) TB Disease in Participants Less Than [<]18 Years of Age at 33 Months After Enrollment [ Time Frame: Baseline up to Month 33 ] [ Designated as safety issue: No ]

Cumulative TB disease rate defined as number of participants ≥18 years old with culture-confirmed TB disease (defined as positive culture for Mycobacterium tuberculosis [MTB]) and those <18 years old with probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, computed tomography [CT] scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for acid-fast bacilli [AFB], or caseating granulomata at autopsy or biopsy) between enrollment and the 990th Day of the Trial (33 months after enrollment, or end of the trial) per 100 participants with (w/)33 months of follow-up calculated using survival analysis methods (Kaplan-Meier approach).

Secondary Outcome Measures:

Cumulative Rate of Culture-Confirmed TB Disease in Participants ≥18 Years of Age AND Culture-Confirmed or Probable (Clinical) TB Disease in Participants <18 Years of Age at 24 Months Following Completion of Study Therapy [ Time Frame: Baseline up to Month 27 (3RPT/INH) or Month 33 (9INH) ] [ Designated as safety issue: No ]

Cumulative TB disease rate was defined as number of participants ≥18 years old with culture-confirmed TB disease (defined as positive culture for MTB) and those <18 years old with probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB], or caseating granulomata at autopsy or biopsy) between enrollment and 24 months after completion of study therapy per 100 participants with up to 33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).

Cumulative Rate of Culture-Confirmed or Probable (Clinical) TB Disease (Regardless of Age) At 33 Months After Enrollment [ Time Frame: Baseline up to 33 Months ] [ Designated as safety issue: No ]

Cumulative TB disease rate was defined as number of participants (regardless of age) with culture-confirmed TB disease (defined as positive culture for MTB]) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB, or caseating granulomata at autopsy or biopsy) between enrollment and the 990th Day of the Trial (33 months after enrollment, or end of the trial) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).

Percentage of Participants With Drug Discontinuation Due to Adverse Drug Reactions Associated With 3RPT/INH or 9INH [ Time Frame: Baseline up to 60 days after the last dose of study drug (Month 5 [3RPT/INH] or Month 11 [9INH]) ] [ Designated as safety issue: Yes ]

Discontinuation of study drug due to an adverse drug reaction associated with either 3RPT/INH or 9INH was defined as discontinuing treatment and/or study due to a treatment-related adverse event (AE) (considered either possibly, probably, or definitely related to the study drug by the investigator).

Percentage of Patients With Grade 3 or 4 Drug Toxicities Associated With 3RPT/INH or 9INH [ Time Frame: Baseline up to 60 days after the last dose of study drug (Month 5 [3RPT/INH] or Month 11 [9INH]) ] [ Designated as safety issue: Yes ]

Drug toxicities (or AEs) were graded using Common Toxicity Criteria (CTC version 2.0, Publish Date April 30, 1999, Cancer Therapy Evaluation Program). Grade 3 and 4 drug toxicities associated with 3RPT/INH or 9INH were defined as treatment-related Grade 3 or 4 AEs (considered either possibly, probably, or definitely related to the study drug by the investigator).

Percentage of Participants With Death Due to Any Cause [ Time Frame: Baseline up to Month 35 ] [ Designated as safety issue: Yes ]

Percentage of Participants With Drug Discontinuation for Any Reason Associated With 3RPT/INH or 9INH [ Time Frame: Baseline up to Month 3 (3RPT/INH) or Month 9 (9INH) ] [ Designated as safety issue: Yes ]

Drug discontinuations for any reason associated with 3RPT/INH or 9INH included all reasons for discontinuation from study treatment, regardless of relationship to treatment.

Percentage of Participants Who Completed the Treatment Regimen [ Time Frame: Baseline up to Month 3 (3RPT/INH) or Month 9 (9INH) ] [ Designated as safety issue: No ]

Completion in the 3RPT/INH arm was defined as: received 12 doses of RPT/INH within 16 weeks (12 weeks optimal). However, participants were considered to have completed therapy if at least 11 doses of RPT/INH had been received (~90%) during the 16-week time period. Completion in the 9INH arm was defined as: received 270 doses of INH within 52 weeks (39 weeks optimal). However, participants were considered to have completed therapy if at least 240 doses of INH were received (~90%) during the 52-week period.

Cumulative Rate of Culture-Confirmed TB Disease in Participants ≥18 Years of Age AND Culture Confirmed or Probable (Clinical) TB Disease Among Participants <18 Years of Age Who Completed Study Phase Therapy Within 33 Months of Enrollment [ Time Frame: Baseline up to Month 33 ] [ Designated as safety issue: Yes ]

Cumulative TB disease rate was defined as number of participants ≥18 years old with culture-confirmed TB disease (defined as positive culture for MTB) and <18 years old with probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB], or caseating granulomata at autopsy or biopsy) between enrollment and 33 months after enrollment (for those who completed therapy within 33 months) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).

Percentage of Participants With Resistance to Study Medications in Isolates of MTB From Participants Who Developed Active TB Disease Within 33 Months of Enrollment [ Time Frame: Baseline up to Month 33 ] [ Designated as safety issue: Yes ]

Drug-susceptibility testing (DST) was performed on isolates of MTB obtained from participants who developed signs and symptoms of active TB disease (including sputum specimens or specimens from appropriate body site for extrapulmonary TB disease). DST was performed at site's local laboratory and sent to Sponsor for confirmatory susceptibility testing. DST included all drugs currently used to treat TB disease, including pyrazinamide (PZA) and fluoroquinolones. Susceptibility was tested for other drugs at the Sponsor laboratory at the following concentrations: INH, 0.02, 1.0, and 5.0 micrograms per milliliter (µg/mL) and rifampin (RIF), 1.0 µg/mL. Isolates resistant to RIF were assumed to be resistant to RPT.

Cumulative TB disease rate was defined as number of HIV-infected participants ≥2 years old with culture-confirmed TB disease (defined as positive culture for MTB) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB], or caseating granulomata at autopsy or biopsy) between enrollment and the 990th day of the trial (33 months after enrollment, or end of the trial) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).

Cumulative Rate of HIV-Infected Participants With Culture-Confirmed or Probable TB Disease at 24 Months After Completion of Study Therapy [ Time Frame: Baseline up to Month 27 (3RPT/INH) or Month 33 (9INH) ] [ Designated as safety issue: No ]

Cumulative TB disease rate was defined as number of HIV-infected participants with culture-confirmed TB (defined as positive culture for MTB) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB], or caseating granulomata at autopsy or biopsy) between enrollment and 24 months after completion of study therapy per 100 participants with up to 33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).

Cumulative Rate of Participants <18 Years Old With Culture-Confirmed or Probable (Clinical) TB Disease Within 33 Months of Enrollment [ Time Frame: Baseline up to Month 33 ] [ Designated as safety issue: No ]

Cumulative TB disease rate was defined as number of participants <18 years old with culture-confirmed TB disease (defined as positive culture for MTB) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB], or caseating granulomata at autopsy or biopsy) between enrollment and the 990th day of the trial (33 months after enrollment, or end of the trial) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).

Cumulative Rate of Participants <12 Years Old With Culture-Confirmed or Probable (Clinical) TB Disease Within 33 Months of Enrollment [ Time Frame: Baseline up to Month 33 ] [ Designated as safety issue: No ]

Cumulative TB disease rate was defined as number of participants <12 years old with culture-confirmed TB disease (defined as positive culture for MTB) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB], or caseating granulomata at autopsy or biopsy) between enrollment and the 990th day of the trial (33 months after enrollment, or end of the trial) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).

The PRIMARY objective of this open-label Phase III clinical trial is to compare the effectiveness of a three-month (12-dose) regimen of weekly rifapentine and isoniazid (3RPT/INH) to the effectiveness of a nine-month (270-dose) regimen of daily isoniazid (9INH) to prevent tuberculosis (TB) among high-risk tuberculin skin-test reactors, including children and HIV-infected persons, who require treatment of latent TB infection (LTBI). The 3RPT/INH regimen will be given under direct observation and the 9INH regimen will be self-administered.

SECONDARY Objectives:

Compare the rates of drug discontinuation due to adverse drug reactions associated with 3RPT/INH and 9INH.

Compare the rates of drug discontinuation for any reason associated with 3RPT/INH and 9INH.

Compare the rates of any grade 3, 4, or 5 drug toxicity associated with 3RPT/INH and 9INH.

Compare treatment completion rates of 3RPT/INH and 9INH. Compare the efficacy (i.e., among persons who complete study-phase therapy) of 3RPT/INH and 9INH.

Compare the effectiveness and tolerability of 3RPT/INH and 9INH in HIV-infected persons.

Compare the effectiveness and tolerability of 3RPT/INH and 9INH in children < 18 years old.

Compare the rates of methadone withdrawal associated with 3RPT/INH and 9INH among persons concomitantly receiving methadone.

Amendment of the study protocol to allow extension of enrollment to children < 12 years old and HIV-infected persons:

For assessment of the primary outcome, development of TB, a sample size of approximately 4,000 persons per arm will be required. To assess tolerability (one of the secondary outcomes) in sub-groups, children less than 12 years old and HIV-infected persons, a sample size of 644 per strata will be required. A sample size of 8,053 patients for the primary outcome was reached on February 15, 2008 (with expected follow-up completion time in 2010), leaving approximately 454 additional young children and 200 HIV-infected persons to be enrolled to achieve the targets of 644 for each group. The additional data on tolerability in those sub-groups will available for analysis in 2013.

Eligibility

Ages Eligible for Study:

2 Years and older

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

INCLUSION criteria:

Males or nonpregnant, non-nursing females > 2 years old.

Tuberculin (PPD) skin test reactors at high risk for developing TB but without evidence of active TB. High-risk reactors are defined as:

Household and other close contacts of persons with culture-confirmed TB who are TST-positive as part of a contact investigation conducted within two years of the date of enrollment. Close contact is defined as > 4 hours in a shared airspace during a one-week period. Among close contacts, a positive TST is defined as > 5 mm induration after 5 TU of PPD placed intradermally using the Mantoux technique.

TST converters--converting from a documented negative to positive TST within a two-year period. This is defined as persons with a tuberculin skin test of > 10 mm within two years of a nonreactive test or persons with an increase of > 10 mm within a two-year period.

HIV-seropositive, TST positive (> 5 mm induration) persons.

Persons with > 2 cm2 of pulmonary parenchymal fibrosis on chest X-ray, no prior history of TB treatment, > 5 mm induration on TST, and 3 sputum cultures negative for M. tuberculosis on final report.

HIV-seropositive close contacts of persons with culture-confirmed TB, regardless of TST status. In addition, HIV-seropositive close contacts of persons with culture-confirmed TB who have a documented history of completing an adequate course of treatment for active TB or latent TB infection, are also eligible.

Willing to provide signed informed consent, or parental consent and participant assent.

EXCLUSION criteria:

Current confirmed culture-positive or clinical TB

Suspected TB (as defined by the site investigator)

Tuberculosis resistant to isoniazid or rifampin in the source case

A history of treatment for > 14 consecutive days with a rifamycin or > 30 consecutive days with INH during the previous 2 years.

A documented history of a completing an adequate course of treatment for active TB or latent TB infection in a person who is HIV-seronegative.

Persons currently receiving or planning to receive HIV-1 protease inhibitors or nonnucleoside reverse transcriptase inhibitors in the first 90 days after enrollment.

Weight < 10.0 kg

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Please refer to this study by its ClinicalTrials.gov identifier: NCT00023452